In persons suffering from nephrogenic diabetes insipidus (hereinafter NDI), generally X-linked type NDI, the gene for the vasopressin receptor is mutated, hence the mutated protein cannot transduce the signal of the presence of vasopressin in circulation when there is an increase in intracellular cAMP and an increase in aquaporin 2 (AQP2) in the membrane.
In vivo, vasopressin is released by the pituitary gland when the organism needs to limit the amount of water eliminated in the urine. Vasopressin binds its V2R receptor on the main cell of the renal collecting duct, determines a transient cAMP increase in the cells and, consequently, shifts the protein AQP2 from the cell cytoplasm towards the apical membrane which faces into the collecting duct. In these conditions a large amount of water is reabsorbed from the pro-urine and returns into the blood, therefore limiting the amount of water which the organism loses in the urine.
The absence of AQP2 on the membrane prevents the reabsorption of water from the pro-urine causing the production of enormous volumes of urine (up to 50 liters/day), exposing the person affected to the constant danger of dehydration and cardiovascular failure.
At present there is no real cure for NDI, in particular for polyuria which accompanies this pathology. The symptoms are kept under control by guaranteeing patients continuous hydration, administering a low-salt diet and treating them with diuretics based on thiazide, alone or in combination with prostaglandin synthesis inhibitors or potassium saver diuretics in order to reduce the volume of urine produced.
The diuretics hydrochlorothiazide and amyloride, used in NDI, reduce the fraction of sodium reabsorbed in the distal tubule causing hypovolemia. To compensate for this situation, the renin-angiotensin-aldosterone system (RAAS) is activated which, by increasing the blood levels of aldosterone, determines a greater reabsorption of sodium in the proximal tubule. Since the reabsorption of sodium in the proximal tubule is accompanied by an isosmotic transport of water, the overall amount of water reabsorbed in the proximal tubule is increased, consequently reducing the volume of urine arriving at the distal nephron. Unfortunately, however, although the administration of said molecules improves the patient's clinical situation, it has serious side effects. In fact, the thiazide is able to reduce the polyuria but, at the same time, it can deplete the deposits of potassium in the organism. The loss of potassium is in itself a very dangerous condition for the organism and must be kept constantly under control by integration of potassium or amyloride-based treatment.
Another treatment consists in prostaglandin synthesis inhibitors, and in particular indometacin, a non-steroid anti-inflammatory drug which, however, can cause migraine and dizziness, increases the risk of gastrointestinal disorders and, when administered in the first year of life, can increase the risk of kidney disease.
Furthermore, indometacin and thiazide determine a reduction in the glomerular filtration rate (GFR) resulting in an increased risk of nephropathy.
The aspecific inhibitors of cyclooxygenases represent an alternative but this treatment can have significant side effects on cardiac function. Furthermore, in patients undergoing this treatment, the volume of urine is considerably reduced but does not drop below 4-12 liters/day.